Osteoporosis affects more than 28 million people in the U.S. and the lifetime risk for osteoporosis-related morbidity is higher than a woman's combined risk for breast, endometrial and ovarian cancer combined. Health care expenditures for osteoporotic patients are currently nearly 13 billion dollars per annum and are predicted to increase markedly due the aging of the population; therefore, it is important to understand the factors that contribute to bone strength and fracture risk. With the advent of skeletal imaging modalities such as high resolution peripheral quantitative computed tomography (HR-pQCT), it is now possible to determine the contribution of bone microarchitecture to the risk for fracture. This R01 application is a new proposal to fund a time-sensitive opportunity to image the Framingham Offspring Cohort using HR-pQCT to understand lifestyle and genetic factors contributing to bone microarchitecture, and to determine if bone microarchitecture provides additional information about fracture risk independent of traditional dual-energy X-ray absorptiometry (DXA). This proposal is time sensitive because the 9th Offspring examination began in the spring of 2011, and we are approved to perform HR-pQCT scans on 2,565 surviving women and men in the Offspring following completion of their 9th study visit. We will measure volumetric BMD, bone microarchitecture and bone strength at the distal radius and distal tibia using three-dimensional HR-pQCT in 1,411 women and 1,154 men in the Framingham Offspring Cohort. Using these data we will determine the association between weight, physical activity, prior fracture, calcium intake, vitamin D intake, and alcohol use and bone microarchitecture in men and women, aged 45-100 years. Because of long-term follow-up of this cohort, we will be able to evaluate the influence of these factors on bone microarchitecture using both short-term and long-term exposure data. In addition we will determine the genetic contribution to bone microarchitecture by performing a genome-wide association study (GWAS) in the Framingham Cohort, a cohort from Sweden, and will obtain genome wide dense genotyping in a third cohort from the Mayo Clinic. Results from a GWAS meta-analysis of these 3 discovery cohorts will be replicated in 5 other cohorts who have the same HR-pQCT-derived measures and available genome-wide genotyping or DNA. Finally, in Framingham as well as the collaborating GWAS cohorts, we will also determine the contribution of bone microarchitecture, and bone strength measured by micro-finite element analysis, to incidence of non-vertebral fragility fracture in women and men, and determine if the association between bone microarchitecture and fracture incidence in women and men is independent of DXA areal BMD and FRAX(R) risk score. This study is significant because it will be the largest community-based study in a well- characterized population to examine risk factors for bone microarchitecture, the first to conduct a genome wide association study of microarchitecture with replication, and the first prospective study to examine the contribution of bone microarchitecture and strength to fracture incidence.